Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression
Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression
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Runx1通过抑制Pu.1表达的负反馈环调节斑马鱼胚胎骨髓命运选择
DOI：
10.1182/blood-2011-12-398362
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发表时间：
2012-05-31
期刊：
影响因子：
20.3
通讯作者：
Wen, Zilong
中科院分区：
文献类型：
--
作者：
Jin, Hao;Li, Li;Wen, Zilong
在骨髓生成中，正确的细胞命运选择对于产生正确数量的不同骨髓亚群至关重要，这些亚群在发育和成年期间表现出广泛的亚群特异性活动。研究表明，髓系细胞的命运选择主要受转录因子的调控，然而，新的内在调控因子及其潜在机制仍有待阐明。斑马鱼胚胎骨髓生成产生中性粒细胞和巨噬细胞，并代表了一个有前途的系统，以获得新的调节机制，在脊椎动物的骨髓命运决定。在这里，我们提出了一个在体内研究细胞命运规范在斑马鱼胚胎骨髓生成通过表征的胚胎改变Pu.1，Runx 1活性单独，或其组合。遗传分析表明，低和高Pu.1活动决定胚胎嗜中性粒细胞和巨噬细胞的命运，分别。Runx 1在斑马鱼中的失活和过表达揭示了Runx 1作为一个关键的胚胎骨髓命运决定因素，有利于中性粒细胞的巨噬细胞的命运。Runx 1由高Pu.1水平诱导，进而反式抑制Pu.1表达，从而构成负反馈回路，形成中性粒细胞与巨噬细胞平衡命运承诺所需的有利Pu.1水平。我们的研究结果定义了一个Pu.1-Runx 1调节环，通过确保适当的Pu.1剂量来控制不同骨髓命运之间的平衡。（血。2012; 119（22）：5239-5249）
Proper cell fate choice in myelopoiesis is essential for generating correct numbers of distinct myeloid subsets manifesting a wide spectrum of subset-specific activities during development and adulthood. Studies have suggested that myeloid fate choice is primarily regulated by transcription factors; however, new intrinsic regulators and their underlying mechanisms remain to be elucidated. Zebrafish embryonic myelopoiesis gives rise to neutrophils and macrophages and represents a promising system to derive new regulatory mechanisms for myeloid fate decision in vertebrates. Here we present an in vivo study of cell fate specification during zebrafish embryonic myelopoiesis through characterization of the embryos with altered Pu.1, Runx1 activity alone, or their combinations. Genetic analysis shows that low and high Pu.1 activities determine embryonic neutrophilic granulocyte and macrophage fate, respectively. Inactivation and overexpression of Runx1 in zebrafish uncover Runx1 as a key embryonic myeloid fate determinant that favors neutrophil over macrophage fate. Runx1 is induced by high Pu.1 level and in turn transrepresses pu.1 expression, thus constituting a negative feedback loop that fashions a favorable Pu.1 level required for balanced fate commitment to neutrophils versus macrophages. Our findings define a Pu.1-Runx1 regulatory loop that governs the equilibrium between distinct myeloid fates by assuring an appropriate Pu.1 dosage. (Blood. 2012; 119(22):5239-5249)